title: Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033.
abstract: Neurofibromatosis Type 1 (NF1) is characterized by the abnormal proliferation of neuroectodermal tissues and the development of certain tumors, particularly neurofibromas, which may progress into malignant peripheral nerve sheath tumors (MPNSTs). Effective pharmacological therapy for the treatment of NF1 tumors is currently unavailable and the prognosis for patients with MPNSTs is poor. Loss of neurofibromin correlates with increased expression of the epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases and these kinases have been shown to promote NF1 tumor-associated pathologies in vivo. We show here that while NF1 MPNST cells have higher EGFR expression levels and are more sensitive to EGF when compared to a non-NF1 MPNST cell line, the ability of the EGFR inhibitor gefitinib to selectively inhibit NF1 MPNST cell proliferation is marginal. We also show that NF1 MPNST proliferation correlates with activated ErbB2 and can be suppressed by nanomolar concentrations of the pan-ErbB inhibitor CI-1033 (canertinib). Consequently, targeting both EGFR and ErbB2 may prove an effective strategy for suppressing NF1 MPNST tumor growth in vivo.
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Dilworth
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.forename: Patricia
authors.initials: P
authors.lastname: Mathieu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tainsky
authors.forename: John J
authors.initials: JJ
authors.lastname: Reiners
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Mattingly
authors.forename: Chad N
authors.initials: CN
authors.lastname: Hancock
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D009025:Morpholines / Q000627:therapeutic use*; D018317:Nerve Sheath Neoplasms / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000150:complications*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D009025:Morpholines; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C420268:Canertinib